The effects of metformin on gut microbiota and the immune system as research frontiers
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Recent studies have revealed that metformin influences gut microbiota and the immune system although neither is a classic target of the drug. This research has revealed complexity not previously appreciated, and opened new research directions. The extent to which immunomodulatory effects and actions on the microbiota are related to each other and account for effects on host energy metabolism remains to be determined. These sites of action may be relevant not only to the efficacy of metformin for its established use in type 2 diabetes, but also to proposed novel indications in oncology and other diseases.
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Metformin has additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, COVID-19, and obesity.
“Aside from its anti-hyperglycemic effects, metformin has an additional benefit for conditions like polycystic ovary syndrome, atherosclerosis, cancer, coronavirus disease 2019 (COVID-19), and obesity (7–14).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [7]
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An obesity-associated gut microbiome with increased capacity for energy harvest
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006) · Nature · doi:10.1038/nature05414 · Cited by 12,444 · see citing works
Diet rapidly and reproducibly alters the human gut microbiome
David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B. E., Ling, A. V., Devlin, A. S., Varma, Y., Fischbach, M. A., et al. (2014) · Nature · doi:10.1038/nature12820 · Cited by 10,100 · see citing works
A metagenome-wide association study of gut microbiota in type 2 diabetes
Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D., et al. (2012) · Nature · doi:10.1038/nature11450 · Cited by 6,762 · see citing works
Gut metagenome in European women with normal, impaired and diabetic glucose control
Karlsson, F. H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C. J., Fagerberg, B., Nielsen, J., & Bäckhed, F. (2013) · Nature · doi:10.1038/nature12198 · Cited by 3,115 · see citing works
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Cheng, S.-C., Quintin, J., Cramer, R. A., Shepardson, K. M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E. J., Martens, J. H. A., Rao, N. A., Aghajanirefah, A., et al. (2014) · Science · doi:10.1126/science.1250684 · Cited by 2,224 · see citing works
Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota
MetaHIT consortium, Forslund, K., Hildebrand, F., Nielsen, T., Falony, G., Le Chatelier, E., Sunagawa, S., Prifti, E., Vieira-Silva, S., Gudmundsdottir, V., et al. (2015) · Nature · doi:10.1038/nature15766 · Cited by 2,116 · see citing works
Human gut microbes impact host serum metabolome and insulin sensitivity
Pedersen, H. K., Gudmundsdottir, V., Nielsen, H. B., Hyotylainen, T., Nielsen, T., Jensen, B. A. H., Forslund, K., Hildebrand, F., Prifti, E., Falony, G., et al. (2016) · Nature · doi:10.1038/nature18646 · Cited by 2,116 · see citing works
Wu, H., Esteve, E., Tremaroli, V., Khan, M. T., Caesar, R., Mannerås-Holm, L., Ståhlman, M., Olsson, L. M., Serino, M., Planas-Fèlix, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4345 · Cited by 1,632 · see citing works
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · see citing works
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501 · see citing works
Self-citationMetformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445 · see citing works
Self-citationAcetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome
Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., Petersen, K. F., Kibbey, R. G., Goodman, A. L., & Shulman, G. I. (2016) · Nature · doi:10.1038/nature18309 · Cited by 1,299 · see citing works
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., Prigaro, B. J., Wood, J. L., Bhanot, S., MacDonald, M. J., et al. (2014) · Nature · doi:10.1038/nature13270 · Cited by 1,284 · see citing works
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096 · see citing works
Metformin: historical overview
Bailey, C. J. (2017) · Diabetologia · doi:10.1007/s00125-017-4318-z · Cited by 1,079 · see citing works
Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism
Cabreiro, F., Au, C., Leung, K.-Y., Vergara-Irigaray, N., Cochemé, H. M., Noori, T., Weinkove, D., Schuster, E., Greene, N. D. E., & Gems, D. (2013) · Cell · doi:10.1016/j.cell.2013.02.035 · Cited by 967 · see citing works
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · see citing works
Metformin and the gastrointestinal tract
McCreight, L. J., Bailey, C. J., & Pearson, E. R. (2016) · Diabetologia · doi:10.1007/s00125-015-3844-9 · Cited by 733 · see citing works
Anti-inflammatory effects of metformin irrespective of diabetes status
Cameron, A. R., Morrison, V. L., Levin, D., Mohan, M., Forteath, C., Beall, C., McNeilly, A. D., Balfour, D. J. K., Savinko, T., Wong, A. K. F., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308445 · Cited by 704 · see citing works
Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria
Bridges, H. R., Jones, A. J. Y., Pollak, M. N., & Hirst, J. (2014) · Biochemical Journal · doi:10.1042/bj20140620 · Cited by 661 · see citing works
Self-citationThe Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
Blagih, J., Coulombe, F., Vincent, E. E., Dupuy, F., Galicia-Vázquez, G., Yurchenko, E., Raissi, T. C., van der Windt, G. J. W., Viollet, B., Pearce, E. L., et al. (2015) · Immunity · doi:10.1016/j.immuni.2014.12.030 · Cited by 659 · see citing works
Moiseeva, O., Deschênes‐Simard, X., St‐Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013) · Aging Cell · doi:10.1111/acel.12075 · Cited by 654 · see citing works
Self-citationNormalization of CD4 + T cell metabolism reverses lupus
Yin, Y., Choi, S., Xu, Z., Perry, D. J., Seay, H. R., Croker, B. P., Sobel, E. S., Brusko, T. M., & Morel, L. M. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa0835 · Cited by 611 · see citing works
Immune-mediated antitumor effect by type 2 diabetes drug, metformin
Eikawa, S., Nishida, M., Mizukami, S., Yamazaki, C., Nakayama, E., & Udono, H. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417636112 · Cited by 553 · see citing works
Metformin as adjunct antituberculosis therapy
Singhal, A., Jie, L., Kumar, P., Hong, G. S., Leow, M. K.-S., Paleja, B., Tsenova, L., Kurepina, N., Chen, J., Zolezzi, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009885 · Cited by 547 · see citing works
Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X., & Delgoffe, G. M. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0103 · Cited by 520 · cited 1× · see citing works
“Another study [38] also documented enhancement of PD-1 blockade as a cancer immunotherapy, but attributed this to a mechanism involving reduction of tumour hypoxia by the biguanide, which in turn was attributed to reduced oxygen consumption secondary to 1664 Diabetologia (2017) 60:1662–1667”
BackgroundInvestigating Metformin for Cancer Prevention and Treatment: The End of the Beginning
Pollak, M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0263 · Cited by 505 · see citing works
Self-citationHirsch, H. A., Iliopoulos, D., & Struhl, K. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221055110 · Cited by 440 · see citing works
Metformin directly acts on mitochondria to alter cellular bioenergetics
Andrzejewski, S., Gravel, S., Pollak, M., & St‐Pierre, J. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-12 · Cited by 424 · see citing works
Self-citationHowell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.009 · Cited by 408 · see citing works
Metformin Activates a Duodenal Ampk-Dependent Pathway to Lower Hepatic Glucose Production in Rats
Duca, F. A., Côté, C. D., Rasmussen, B. A., Zadeh-Tahmasebi, M., Rutter, G. A., Filippi, B. M., & Lam, T. K. T. (2015) · Nature Medicine · doi:10.1038/nm.3787 · Cited by 402 · see citing works
Kordes, S., Pollak, M., Zwinderman, A. H., Mathôt, R. A. A., Weterman, M. J., Beeker, A., Punt, C. J. A., Richel, D. J., & Wilmink, J. W. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00027-3 · Cited by 387 · see citing works
Self-citationBrunkwall, L., & Orho‐Melander, M. (2017) · Diabetologia · doi:10.1007/s00125-017-4278-3 · Cited by 360 · see citing works
Buse, J. B., DeFronzo, R. A., Rosenstock, J., Kim, T., Burns, C., Skare, S., Baron, A., & Fineman, M. (2016) · Diabetes Care · doi:10.2337/dc15-0488 · Cited by 325 · see citing works
Gui, D. Y., Sullivan, L. B., Luengo, A., Hosios, A. M., Bush, L. N., Gitego, N., Davidson, S. M., Freinkman, E., Thomas, C. J., & Vander Heiden, M. G. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.006 · Cited by 323 · see citing works
The Role of the Immune System in Metabolic Health and Disease
Zmora, N., Bashiardes, S., Levy, M., & Elinav, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.006 · Cited by 323 · see citing works
The Microbiome and Risk for Obesity and Diabetes
Komaroff, A. L. (2016) · JAMA · doi:10.1001/jama.2016.20099 · Cited by 294 · see citing works
Repurposing metformin: an old drug with new tricks in its binding pockets
Pryor, R., & Cabreiro, F. (2015) · Biochemical Journal · doi:10.1042/bj20150497 · Cited by 280 · see citing works
Grasset, E., Puel, A., Charpentier, J., Collet, X., Christensen, J. E., Tercé, F., & Burcelin, R. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.013 · Cited by 280 · see citing works
Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?
Klil-Drori, A. J., Azoulay, L., & Pollak, M. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.120 · Cited by 207 · see citing works
Self-citationCurrent understanding of metformin effect on the control of hyperglycemia in diabetes
An, H., & He, L. (2016) · Journal of Endocrinology · doi:10.1530/joe-15-0447 · Cited by 202 · see citing works
Negrotto, L., Farez, M. F., & Correale, J. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2015.4807 · Cited by 198 · see citing works
Are Metformin Doses Used in Murine Cancer Models Clinically Relevant
Chandel, N. S., Avizonis, D., Reczek, C. R., Weinberg, S. E., Menz, S., Neuhaus, R., Christian, S., Haegebarth, A., Algire, C., & Pollak, M. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.03.010 · Cited by 176 · see citing works
Transporters Involved in Metformin Pharmacokinetics and Treatment Response
Liang, X., & Giacomini, K. M. (2017) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.04.078 · Cited by 169 · see citing works
Lee, S.-Y., Moon, S., Kim, E., Seo, H.-B., Yang, E., Son, H., Kim, J. K., Min, J., Park, S., & Cho, M. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1403088 · Cited by 144 · see citing works
Kim, S. H., Li, M., Trousil, S., Zhang, Y., di Magliano, M. P., Swanson, K. D., & Zheng, B. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.03.033 · Cited by 140 · see citing works
Rajeshkumar, N. V., Yabuuchi, S., Pai, S. G., Oliveira, E. D., Kamphorst, J. J., Rabinowitz, J. D., Tejero, H., Al‐Shahrour, F., Hidalgo, M. M., Maitra, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1115 · Cited by 90 · see citing works
Buse, J. B., Rodbard, H. W., Serrano, C. T., Luo, J., Iványi, T., Bue‐Valleskey, J. M., Hartman, M. L., Carey, M. A., & Chang, A. M. (2015) · Diabetes Care · doi:10.2337/dc15-1531 · Cited by 82 · see citing works
Bridges, H. R., Sirviö, V. A., Agip, A.-N. A., & Hirst, J. (2016) · BMC Biology · doi:10.1186/s12915-016-0287-9 · Cited by 81 · see citing works
Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome
Wang, P., Li, J., Walcott, F. L., Kang, J., Starost, M. F., Talagala, S. L., Zhuang, J., Park, J., Huffstutler, R. D., Bryla, C., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci88668 · Cited by 64 · see citing works
Self-citationGoldberg, R. B., Temprosa, M. G., Mather, K. J., Orchard, T. J., Kitabchi, A. E., & Watson, K. E. (2014) · Diabetes Care · doi:10.2337/dc13-2471 · Cited by 55 · see citing works
Metformin and Pancreatic Cancer: A Clue Requiring Investigation
Pollak, M. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0694 · Cited by 32 · see citing works
Self-citationAgrawal, S., & Gupta, Y. (2016) · Diabetes Care · doi:10.2337/dc16-1340 · Cited by 25 · see citing works
Jailing, O., & Olsen, C. (1984) · Acta Pharmacologica et Toxicologica · doi:10.1111/j.1600-0773.1984.tb01938.x · Cited by 19 · see citing works
ANTIMICROBIAL ACTIVITIES OF BIGUANIDES*
Weinberg, E. D. (1968) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1968.tb27733.x · Cited by 19 · see citing works
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Isnard, S., Lin, J., Fombuena, B., Ouyang, J., Varin, T. V., Richard, C., Marette, A., Ramendra, R., Planas, D., Raymond Marchand, L., et al. (2020) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofaa338 · Cited by 51 · see citing works
GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin
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- Authors
- Pollak, M.
- Venue
- Diabetologia
- Published
- 2017-08-02
- Volume
- 60
- Issue
- 9
- Pages
- 1662-1667
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2741858880
- Cited by
- 98
- References
- 55
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 9 · 2023: 13 · 2022: 8 · 2021: 15 · 2020: 24 · 2019: 10 · 2018: 7 · 2017: 3
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- metformin, gut microbiota, immune system, immunomodulation, energy metabolism, type 2 diabetes, cancer therapy
- MeSH terms
- Gastrointestinal Microbiome, Humans, Metformin, Microbiota
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